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Relationship: 3141

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increase, Mitochondrial dysfunction leads to Increase, ROS

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increase, Mitochondrial dysfunction

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increase, ROS

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis	adjacent	High		Travis Karschnik (send email)	Under development: Not open for comment. Do not cite
Mitochondrial complex inhibition leading to liver injury	adjacent	High	High	Wanda van der Stel (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
Rattus norvegicus	Rattus norvegicus	Moderate	NCBI
Mus musculus	Mus musculus	Moderate	NCBI
Homo sapiens	Homo sapiens	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Mitochondria play a role in stress responses and can produce ROS when damaged. Mitochondria are indeed a major source of ROS (Yuan et al., 2013). ROS production is related to the level of ETC (Fleury et al., 2002); it is elevated when electron transport is reduced, which occurs in pathological situations (Wallace 2005).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. The KER is referenced in publications which were cited in the originating work for the putative AOP "Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis", Katherine von Stackelberg & Elizabeth Guzy & Tian Chu & Birgit Claus Henn, 2015. Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework, Risk Analysis, John Wiley & Sons, vol. 35(6), pages 971-1016, June.

This evidence was assembled from a literature search relying on standard search engines such as PubMed, Web of Science, Google Scholar, Environmental Index, Scopus, Toxline, and Toxnet and the search strategy included terms related to metal mixtures, individual metals (e.g., arsenic, lead, manganese, and cadmium), neurodevelopmental health outcomes, and associated Medical Subject Headings (MeSH) terms.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

A phenotype that is commonly associated with mitochondrial dysfunction, and in fact with many age-related diseases, is the accumulation of damage attributable to the buildup of reactive oxygen species (Leadsham et al., 2013). Indeed, a vicious cycle of decline in which ROS arising from the mitochondrial electron transport chain (ETC) leads to the damage to mitochondrial DNA and a resultant increase in radical production provides the cornerstone of the much scrutinized free radical theory of aging (Harman 1956). However, ROS also serve as important signaling molecules that can promote longevity in C. elegans (Schulz et al., 2007) and also in yeast (Mesquita et al., 2010).

Alterations in mitochondrial physiology could be involved in programmed cell death (PCD). First, reactive oxygen species (ROS) may participate as effector molecules in PCD (Hockenbery et al., 1993; Kane et al., 1993; Sandstrom et al., 1994).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Lopez et al. (2006) showed that in cortical neurons, cadmium exposure induced cellular death, which was, in part, reversed by vitamin C, an antioxidant agent. The apoptosis produced by cadmium was reversed by vitamin C while the necrosis was not affected by this antioxidant molecule. It also appears that in the apoptotic mechanism mediated by cadmium, but not in the necrotic mechanisms, oxidative stress could be implicated. The ability of cadmium to induce oxidative stress in cortical neurons is aided by the induction of ROS by this cation. Cortical neurons treated with cadmium ions at concentrations between 1 and 100 μM, in either the absence or in the presence of serum in the treatment medium, generated ROS. The induction of ROS in these cells type could be mediated by mitochondria alterations because cadmium produces a breakdown of the mitochondrial membrane potential. The decreases in ATP levels and in the mitochondria membrane potential began at 10 and 50 μM cadmium ion, respectively, while the ROS formation was detected at lower doses (100 nM or 1 μM). These results likely indicate that ROS formation occurs or it is detectable before the toxic events on mitochondrial function that lead to the breakdown in mitochondrial potentials.

Zamzami et al. (1995) concluded that at a final level, the shrinkage of ΔΨ_m^lowHE⁺ cells is selectively inhibited by substances that suppress mitochondrial ROS generation (rotenone, ruthenium red), as well as by antioxidants such as the vitamin E derivative trolox, alone or incombination with L-ascorbate, or the radical scavenger N-t-butyl-alpha-phenylnitrone. This observation confirms that ROS are PCD effector molecules. In synthesis, these data indicate that ΔΨ_m reduction and enhanced mitochondrial ROS generation indeed represent two clearly distinct phases of the preapoptotic process. Only after ΔΨ_mhas dropped are ROS generated and do they participate in the perturbation of mitochondrial membranes, as well as in later manifestations of PCD such as cell shrinkage.

Zamazim et al. (1995) went on to state that reduction in ΔΨ_m and subsequent KOS hyperproduction are observed in several in vitro models of physiological PCD, i.e., models in which nontoxic agents were used to induce PCD in susceptible target cells: TNF-a in U937 cells and anti-IgM in WEHI 231 pre-B cells, as well as CD3 cross-linking in T cell hybridomas. Ceramide, a second messenger involved in the mediation of some PCD types (Obeid et al., 1993; Haimovitz-Friedman et al., 1994), also causes these effects. In all of these systems, alterations in mitochondrial function precede DNA fragmentation and nuclear DNA loss. Thus, it appears that mitochondrial derangement is a constant feature of PCD occurring independently of the PCD-inducing stimulus.

Zhang et al. (2004) reported that Mn²⁺ exposure inhibited the complexes I–IV compared to the control. The inhibition of the respiratory activity by Mn²⁺ is accompanied by a substantial increase of ROS production rate. They went on to report that NAC, GSH and vitamin C are effective in the prevention of Mn²⁺-induced ROS production and decreases of complexes I–IV activity in isolated mitochondria. Preventive effects of NAC and GSH reveal that cellular GSH are crucial for protection against Mn²⁺-induced toxicity.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

List of the literature that was cited for this KER description. More help

E. López, C. Arce, M.J. Oset-Gasque, S. Cañadas, M.P. González Cadmium induces reactive oxygen species generation and lipid peroxidation in cortical neurons in culture Free Radic. Biol. Med., 40 (2006), pp. 940-951

Fleury C, Mignotte B, Vayssiere JL (2002) Mitochondrial reactive oxygen species in cell death signaling. Biochimie 84: 131–141.

Haimovitz-Friedman, A., C.-C. Kan, D. Ehleitner, K.S. Persand, M. McLoughlin, Z. Fuks, and K.N. Kolesnick. 1994. Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J. Ex F Med. 180:525-535.

Harman, D. (1956). Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11, 298–300.

Hockenbery, D.M., Z.N. Oltvai, X.-M. Yin, C.L. Milliman, and S.J. Korsmeyer. 1993. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 75:241-251.

Kane, D.J., T.A. Sarafian, K. Anton, H. Hahn, E.B. Gralla, J.S. Valentine,T. Ord, and D.E. Bredesen. 1993. Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science (Wash. DC). 262:1274-1277

Leadsham, Jane E., et al. "Loss of cytochrome c oxidase promotes RAS-dependent ROS production from the ER resident NADPH oxidase, Yno1p, in yeast." Cell metabolism 18.2 (2013): 279-286.

Mesquita, A., Weinberger, M., Silva, A., Sampaio-Marques, B., Almeida, B., Leao, C., Costa, V., Rodrigues, F., Burhans, W.C., and Ludovico, P. (2010). Caloric restriction or catalase inactivation extends yeast chronological lifespan by inducing H2O2 and superoxide dismutase activity. Proc. Natl. Acad. Sci. USA 107, 15123–15128.

Obeid, L.M., C.M. Linardic,L.A. Karolak, and Y.A. Hannun. 1993. Programmed cell death induced by ceramide. Science (Wash. DC). 259:1769-1771.

Sandstrom, P.A., M.D. Mannie, and T.M. Buttke. 1994. Inhibition of activation-induced death in a T cell hybridoma by thiol antioxidants: oxidative stress as a mediator of apoptosis. J. Leukocyte Biol. 55:221-226.

Schulz, T.J., Zarse, K., Voigt, A., Urban, N., Birringer, M., and Ristow, M. (2007). Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 6, 280–293.

Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39: 359–407.

Yuan, Yan, et al. "Cadmium-induced apoptosis in primary rat cerebral cortical neurons culture is mediated by a calcium signaling pathway." PloS one 8.5 (2013): e64330.

Zamzami, Naoufal, et al. "Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death." The Journal of experimental medicine 182.2 (1995): 367-377.

Zhang, Surong, Juanling Fu, and Zongcan Zhou. "In vitro effect of manganese chloride exposure on reactive oxygen species generation and respiratory chain complexes activities of mitochondria isolated from rat brain." Toxicology in vitro 18.1 (2004): 71-77.